Stromal upregulation of SOX2 promotes tumorigenesis through the generation of a SFRP1/2-expressing cancer-associated fibroblast population

SUMMARY Cancer-associated fibroblasts (CAFs) promote tumor malignancy, but the precise transcriptional mechanisms regulating the acquisition of the CAF phenotype are not well understood. We show that the upregulation of SOX2 is central to this process, which is repressed by protein kinase C ζ (PKC ζ ). PKC ζ deficiency activates the reprogramming of colonic fibroblasts to generate a predominant SOX2-dependent CAF population expressing the WNT regulator Sfrp2 as its top biomarker. Therefore, the PKC ζ -SOX2 axis emerges as a critical step in the control of CAF pro-tumorigenic potential. eTOC Kasashima et al. describe a molecular mechanism whereby the loss of PKCz in the stroma upregulates SOX2 to activate the reprogramming of colonic fibroblasts generating a SFRP1/2-expressing CAF population. This population supports epithelial tumor progression, revealing vulnerabilities in mesenchymal CMS4 colorectal cancer. role of the in phenotype in show that PKC ζ , but not PKC λ / ι , expression is downregulated by TGF in the loss